WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 =
`
`(11) International Publication Number:
`
`WO 93/00951
`
`A61M 11/00, 15/00, 16/00
`
`(43) International Publication Date:
`
`21 January 1993 (21.01.93)
`
`(21) International Application Number:
`
`PCT/US92/05621
`
`(22) International Filing Date:
`
`2 July 1992 (02.07.92)
`
`(81) Designated States: AU, CA, JP, KR, European patent (AT,
`BE, CH, DE, DK, ES, FR, GB, GR, IT, LU, MC, NL,
`SE).
`
`
`
`A device for accurately delivering aerosolized doses of a medicament disperses a measured amount of drug (40) in a mea-
`sured volume of carrier gas (22) and transfers the resulting aerosol to a chamber (42) prior to inhalation by a patient. The cham-
`ber (42) is filled efficiently with the aerosol, and inhalation by the patient draws the aerosol dose into the lungs. This is followed
`by the inhalation of atmospheric air (96) that will push the initial dose well into the lung interior. The apparatus optimally in-
`cludes a dose regulator (13a), 3 counter (130), a clock (l3e), a dose memory (30) and a signal (32) to indicate when a dose is ready
`by inhalation. Optimal chamber designs are disclosed.
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(30) Priority data:
`724,915
`
`2 July 1991 (02.07.91)
`
`US
`
`(71) Applicant: INHALE, INC. [US/US]; 3603-D Haven Ave-
`nue, Menlo Park, CA 94025 (US).
`
`; 330 Emerald Avenue, San
`(72) Inventors: PATTON, John, S.
`Carlos, CA 94070 (US). PLATZ, Robert, M. ; 324 Valdez
`Avenue, Half Moon Bay, CA 94019 (US).
`
`(74) Agent: HESLIN, James, M.; Townsend and Townsend,
`One Market Plaza, 20th FL, Steuart Tower, San Francis-
`co, CA 94105 (US).
`
`(54) Title: METHOD AND DEVICE FOR DELIVERING AEROSOLIZED MEDICAMENTS
`
`(57) Abstract
`
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`Mudagamtr
`
`l'inland
`France
`(iahon
`United Kingdom
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Democratic People's Republic
`of Korea
`Republic of Korea
`1 ieelttcnstein
`bri Lattkit
`Luxembourg
`Monaco
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCl‘ on the ftont pages of pamphlets publishing international
`applications under the PCT.
`
`A'l'
`
`BB
`BE
`8F
`BC
`BJ
`8R
`CA
`
`Austria
`Aualralia
`Barbados
`Belgium
`Burkina Paw
`Bulgaria
`Berlin
`Brazil
`('anada
`Central African Republic
`(‘ongu
`Switzerland
`('51: d‘lvuire
`Cameroon
`(fuchoslovakia
`Germany
`Denmark
`Spain
`
`'
`
`'
`
`.
`
`Mali
`Mongolia
`Mauritania
`Malawi
`Netltcrlanda
`Norway
`Poland
`Romania
`Russian Federation
`Sudan
`Sweden
`Senegal
`Soviet Union
`Chad
`Togo
`United States of America
`
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`W0 93/00951
`
`PCT/ US92/0562]
`
`METHOD AND DEVICE FOR DELIVERING
`AEROSOLIZED MEDICAMENTS
`
`The present invention is a continuation-in-part of
`application Serial No. 07/724,915, filed on July 2, 1991,
`the
`full disclosure of which is incorporated herein by reference.
`
`1.
`
`Field of the Invention
`
`EA2EQEQEEQ_QZ_!§E_IEEEEZIQE
`
`This invention relates to a structure and method of
`administering precisely measured doses of a therapeutic by
`inhalation.
`
`An accurate mechanism for delivering precise doses of
`
`aerosol drugs into the interior of human lungs has been an
`objective of many workers in the art. One of the most popular
`aerosol delivery devices is the propellant-driven metered dose
`inhaler (MDI), which releases a metered dose of medicine upon
`each actuation. Although these devices may be useful for many
`medicines, only a small variable percentage of the medicine is
`delivered to the lungs.
`The high linear speed with which the
`dosage leaves the device, coupled with incomplete evaporation
`of the propellants, causes much of the medicine to impact and
`stick to the back of the throat. This impacting and sticking
`creates a local concentration of drugs much of which is
`
`In the trade, this impact area is called
`eventually swallowed.
`a "hot spot" and can cause local immune-suppression and the
`development of fungal infections with bronchosteriods. With
`
`broncodilators, for instance,
`
`the swallowed dose can contribute
`
`to unwanted systemic side effects such as tremor and
`
`
`
`tachycardia.
`
`MDI's also require a degree of coordination between
`activation and inhalation. Many patients are incapable of this
`task, especially infants, small children and the elderly.
`In
`an effort to overcome some of the above limitations of MDI's,
`others have interposed "spacers" between the conventional MDI
`
`The primary function of these spacers is to
`and the patient.
`provide extra volume to allow time for increased propellant
`droplet evaporation prior to inhalation and to reduce the
`
`velocity and impact of the medicine at the back of the throat.
`
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`
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`
`Although spacers do compensate for some of the inadequacies in
`
`the conventional MDI, it has been found that much of the
`
`medicine that may have ordinarily been deposited on the throat
`
`remains in the spacer and the total dose deposited in the lungs
`
`is small.
`
`It has been found that only approximately 8% of the
`
`medicine reaches the interior of the lung with conventional
`
`MDI's. Approximately 13% of the medicine reaches the lung when
`
`it is equipped with a spacer.
`
`other workers in the art have attempted to provide a
`
`metered dose of a medicant by using dry powder inhalers (DPI).
`
`Such devices normally rely on a burst of inspired air that is
`
`drawn through the unit. However,
`
`these units are disadvantaged
`
`in that the force of inspiration varies considerably from
`
`person to person.
`
`Some patients are unable to generate
`
`sufficient flow to activate the unit. DPI's have many of the
`
`
`
`disadvantages of MDI's in that a large percentage of the
`
`medicant is deposited in the throat because of incomplete
`
`particle dispersion and the impact at the rear of the throat.
`
`Although pocket size MDI's and DPI's are very convenient they
`
`have disadvantages some of which are cited above.
`
`other workers in the art have refined aqueous
`
`nebulization delivery systems. Although such systems require a
`
`continuous gas compressor, making them less portable than the
`
`MDI's and the DPI's, many nebulizers provide a low velocity
`
`aerosol which can be slowly and deeply inhaled into the lungs.
`
`Precision of dosage delivery, however, remains a serious
`
`problem and it is difficult to determine how much medicament
`
`the patient has received. Most nebulizers operate continuously
`
`during inhalation and exhalation. Dosage is dependent on the
`
`number and duration of each breath.
`
`In addition to breath
`
`frequency and duration,
`
`the flow rate, i.e., the strength of
`
`the breath that is taken from a nebulizer can effect the
`
`particle size of the dose inhaled.
`
`The patient's inhalation
`
`acts as a vacuum pump that reduces the pressure in the
`
`nebulizer.
`
`A strong breath can draw larger unwanted particles
`
`of medicant out of the nebulizer.
`
`A weak breath, on the other
`
`hand, will draw insufficient medicant from the nebulizer.
`
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`\V()93/00951
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`3
`
`P(3f/[fl392/05621
`
`Electra-mechanical ventilators and devices have also
`been used in recent years to deliver inhalable materials to a
`patient. These devices permit mixing of a nebulized medicant
`into breathing circuit air only during pre-set periods of a
`breathing cycle. An example of this type of machine is the
`system taught by Edgar et al., in their U.S. Patent No.
`
`4,677,975,
`
`issued in July of 1987 where a nebulizer is
`
`
`
`connected to a chamber which in turn is connected to a
`
`A breath
`mouthpiece, an exhaust valve, and an inlet valve.
`detector and timer are used to deliver nebulized materials to
`the patient during a portion of the breathing cycle. However,
`in Edgar and others of this type,
`the patient's intake strength
`can effect the nebulizer operation with many of the
`consequences heretofore mentioned. Moreover,
`the amount of
`nebulized material delivered in each breath can vary
`In a
`significantly, contributing to inaccurate total dosages.
`modification of Edgar et al. (Elliott, et a1.
`(1987) Australian
`Paediatr. J. 23:293-297), filling of the chamber with aerosol
`is timed to occur during the exhalation phase of the breathing
`cycle so that the patient is not inhaling through the device
`during nebulization. This design, however, requires that the
`patient maintain a constantly rhythmic breathing pattern into
`and out of the device, which is inconvenient and can
`contaminate the device with oval microbes. Moreover, no
`provision is made on the devices to efficiently capture the
`aerosol in the chamber so that as many as 80 breaths or more
`must be taken to obtain a dose of medication.
`
`The delivery of therapeutic proteins and polypeptides
`by inhalation presents additional problems. Many protein drugs
`are produced recombinantly and can thus be very expensive.
`It
`is therefore important that loss of a protein drug within the
`delivery device be reduced or preferably eliminated. That is,
`substantially all drug initially charged within the device
`should be aerosolized and delivered to the patient without loss
`within the device or released externally of the device.
`The
`
`In
`particular, protein drugs should be completely dispersed into
`
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`WO 93/00951
`
`4
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`PCT/US92/05621
`
`small particles in the preferred 1 pm to 5 gm size range which
`
`is preferentially delivered to the alveolar region of the
`
`lungs.
`
`The amount of protein drug delivered to the patient in
`
`each breath must also be precisely measured so that the total
`
`be desirable to permit the delivery of highly concentrated
`
`aerosols of the protein drug so that the number of breaths
`
`required for a given dosage can be reduced,
`
`thus increasing
`
`accuracy and reducing the total time required for
`
`administration.
`
`2. Description of the Background Art
`
`dosage of drug can be accurately controlled. Finally, it will
`
`
`
`U.S. Patent Nos. 4,926,852 and 4,790,305, describe a
`
`type of "spacer" for use with a metered dose inhaler.
`
`The
`
`spacer defines a large cylindrical volume which receives an
`
`axially directed burst of drug from a propellant-driven drug
`
`supply. U.S. Patent No. 5,027,806, is an improvement over the
`
`'852 and '305 patents, having a conical holding chamber which
`
`receives an axial burst of drug. U.S. Patent No. 4,624,251,
`
`describes a nebulizer connected to a mixing chamber to permit a
`
`continuous recycling of gas through the nebulizer. U.S. Patent
`
`No. 4,677,975,
`
`is described above. European patent application
`
`347,779 describes an expandable spacer for a metered dose
`
`inhaler having a one-way valve on the mouthpiece.
`
`WO 90/07351
`
`describes a dry powder oral inhaler having a pressurized gas
`
`source (a piston pump) which draws a measured amount of powder
`
`into a venturi arrangement.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides methods and apparatus
`
`for producing an aerosolized dose of a medicament for
`
`subsequent inhalation by a patient. The method comprises first
`
`dispersing a preselected amount of the medicament in a
`
`predetermined volume of gas, usually air.
`
`The dispersion may
`
`be formed from a liquid, for example by injecting an air stream
`
`through a liquid reservoir of the drug, or from a dry powder,
`
`for example by drawing the powder into a flowing air stream
`
`from a reservoir using a venturi or other dispersion nozzle.
`
`The present'invention relies on flowing substantially the
`
`entire aerosolized dose into a chamber which is initially
`
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`5
`
`filled with air and open through a mouthpiece to the ambient.
`
`The aerosolized dose of medicament flows into the chamber under
`
`conditions which result in efficient displacement of the air
`
`By "efficient displacement," it
`with the aerosolized material.
`is meant that at least 40% by weight of the aerosolized
`
`material entering the chamber will remain aerosolized and
`
`suspended within the chamber,
`
`thus being available for
`
`subsequent inhalation through the mouthpiece.
`
`It is further
`
`meant that very little or none of the aerosolized material will
`
`escape from the chamber prior to inhalation by the patient.
`Efficient displacement of air and filling of the chamber can be
`
`achieved by proper design of the chamber, as discussed below.
`
`After the aerosolized medicament has been transferred
`
`
`
`to the chamber,
`
`the patient will inhale the entire dose in a
`
`single breath. Usually,
`
`the total volume of aerosolized
`
`medicament and air within the chamber will be substantially
`less than an average patient's inspiratory capacity, typically
`being about 100 ml to 750 ml.
`In this way,
`the patient can
`first inhale the entire amount of drug present in the dose and
`continue in the same breath to take in air from the ambient
`
`which passes through the chamber and which helps drive the
`medicament further down into the alveolar region of the lungs.
`Conveniently,
`the steps of aerosolizing the medicament, filling
`the chamber, and inhalation of the chamber contents may be
`repeated as many times as necessary to provide a desired total
`
`dosage of the medicament for the patient.
`
`Apparatus according to the present invention comprise
`both a dispersion device for aerosolizing the medicament,
`either from a liquid or dry powder formulation of the
`medicament, and a chamber having an air inlet and patient
`mouthpiece for receiving the aerosolized medicament from the
`
`The chamber is designed and connected to
`dispersion device.
`the dispersion device in such a way that the aerosolized
`medicament will flow into the chamber and efficiently displace‘
`the internal air volume, as described above. The volume of the
`
`chamber will be at least as large as the maximum expected
`volume of aerosolized medicament to be transferred from the
`
`dispersion device. Usually,
`
`the chamber volume will be greater
`
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`6
`
`than the aerosol volume in order to reduce losses through the
`
`mouthpiece, with exemplary chamber volumes being in the range
`
`from 100 ml to 750 ml, as described above. The volume of
`
`aerosolized medicament will usually be in the range from 50 ml
`
`to 750 ml when the dispersion device is a liquid nebulizer and
`
`from 10 ml to 200 ml when the dispersion device is a dry powder
`
`disperser, as described in more detail below.
`
`In order to
`
`enhance efficient filling, the chamber will preferably define
`
`an internal flow path so that the entering aerosolized
`
`medicament will follow the path and displace air within the
`
`chamber without substantial loss of the medicament through the
`
`mouthpiece. Alternatively,
`
`the chamber may include a baffle
`
`which acts to entrap a high velocity aerosol, particularly
`
`those associated with dry powder dispersions.
`
`In a preferred aspect,
`
`the chamber is generally
`
`cylindrical and is connected to the dispersion device by a
`
`tangentially disposed aerosol inlet port located at one end of
`
`the cylinder The mouthpiece is then located at the opposite
`
`end of the cylinder, and aerosolized medicament flowing into
`
`the chamber will follow a generally vortical flow path defined
`
`by the internal wall of the chamber.
`
`By also providing an
`
`ambient air inlet at the same end of the cylindrical chamber,
`
`the patient can first inhale the medicament and thereafter
`
`breath in substantial amounts of ambient air, thus sweeping the
`
`interior of the chamber to efficiently remove substantially all
`
`aerosolized medicament present and help drive the medicament
`
`further into the patient's lungs.
`
`In further preferred aspects,
`
`the ambient air inlet
`
`of the chamber will be protected, typically through a one-way
`
`valve structure which permits air inflow but blocks aerosol
`
`outflow, so that aerosol will not be lost as it enters the
`
`chamber.
`
`The chamber may also comprise vortical baffles,
`
`typically in the form of an axially aligned tube or conical
`
`cylinder within the interior of the chamber,
`
`to restrict
`
`dispersion of the aerosol within the chamber and improve
`
`
`
`delivery efficiency.
`
`In an alternate preferred aspect, the chamber is
`
`generally cylindrical with an axially oriented aerosol inlet
`
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`WO 93/00951
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`PCT/US92/05621
`
`The mouthpiece is located at the
`port located at one end.
`other end of the cylinder, and an internal baffle is located
`between the aerosol inlet and the mouthpiece to prevent direct
`passage of the aerosol to the mouthpiece (which could result in
`loss of medicament well before the chamber has been efficiently
`filled).
`The internal baffle is preferably hemispherical in
`shape with a concave surface oriented toward the aerosol inlet.
`Such a construction has been found particularly useful in
`
`The chamber further includes a tangential ambient air inlet
`port disposed in the chamber wall between the aerosol inlet and
`the internal baffle.
`By inhaling through the mouthpiece,
`the
`patient is able to establish a vortical flow of ambient air
`which will sweep the contained aerosol past the baffle and
`through the mouthpiece.
`
`
`
`the
`
`In yet another aspect of the present invention,
`apparatus for producing aerosolized doses of a medicament
`comprises the dispersing device, means for delivering
`pressurized gas to the dispersing device,
`the aerosol chamber,
`and a controller capable of selectively controlling the amount
`of pressurized air delivered to the dispersing device in order
`to produce the desired single doses of medicament and deliver
`said doses to the chamber.
`The controller may include means
`for timing the actuation of a compressor or means for
`controlling the amount of gas released from a pressurized
`cylinder, as well as a mechanism for counting and displaying
`the number of doses delivered from the chamber during a
`particular period of use. Still further,
`the controller may
`include a microprocessor and a keypad for inputting information
`to the microprocessor.
`
`the controller may comprise a
`In exemplary devices,
`timer connected to selectively actuate a valve, such as a
`solenoid valve, on a gas cylinder. Alternatively,
`the timer
`may turn on and off an air compressor to regulate the amount of
`air delivered to the dispersing device.
`In portable and hand-
`held apparatus, the controller may simply be a release button
`or mechanism that actuates a spring or air driven piston to
`
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`PCT/ US92/05621
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`8
`
`deliver a specific amount of gas.
`
`The controller could also be
`
`a metered valve which could release a fixed amount of liquid
`
`propellant to the dispersing device (in a manner similar to a
`
`metered dose inhaler).
`
`The method and the apparatus of the present invention
`
`are particularly effective for delivering high value drugs,
`
`such as polypeptides and proteins,
`
`to a patient with minimal
`
`loss of the drug in the device. Moreover,
`
`the method and
`
`device provide for a very accurate measurement and delivery of
`
`the doses, while employing relatively simple and reliable
`
`equipment. Further advantages of the present invention include
`
`the ability to vary the total dosage delivered, either by
`
`controlling the number of breaths taken or by controlling the
`
`amount of medicament in each breath. Still further,
`
`the method
`
`and device of the present invention permit the delivery of
`
`relatively concentrated doses of the medicament in order to
`
`reduce the amount of time and number of breaths required for
`
`the delivery of a total dosage of the medicament, particularly
`
`when using dry powder medicament formulations.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Fig. 1 is a schematic-diagrammatic view of the
`
`invention;
`
`Fig. 2 is a diagrammatic cross-sectional view of a
`
`holding chamber;
`
`Fig.
`
`3
`
`Fig. 4
`
`'
`
`'
`
`a diagrammatic view of the holding chamber;
`
`a cross-section along the line 4-4 of
`
`
`
`Fig. 3;
`
`Fig. 3;
`
`Fig. 5 '
`
`a cross-section along the line 5-5 of
`
`Fig. 6A-6D are diagrammatic views disclosing the
`
`stages of operation; and
`
`Fig. 7 illustrates a venturi nozzle which may be used
`
`for dispersing dry powder medicament formulations when used in
`
`systems constructed in accordance with the principles of the
`
`present invention;
`
`Figs. 8-11 illustrate various exemplary chambers
`which may be used in the aerosol delivery systems of the
`
`present invention.
`
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`9
`
`DESCRIPTION OF THE SPECIFIC EMBODIMENTS
`
`The method and device of the present invention are
`
`useful for delivering a wide variety of medicaments, drugs,
`biologically active substances, and the like, to a patient's
`lung, particularly for systemic delivery of the medicament or
`the like.
`The present invention is particularly useful for
`delivering high value medicaments and drugs, such as proteins
`and polypeptides, where efficient delivery and minimum loss are
`
`of great concern.
`
`The apparatus of the present invention will usually
`comprise the following basic components:
`a means for producing
`a metered volume of gas, a mixing chamber for generating an
`aerosol bolus from either a liquid or a powder, a reservoir
`
`that contains the medicament, and a holding chamber that
`efficiently captures the aerosol bolus to maintain the
`
`aerosolized particles in suspension and allow a patient to
`inhale the aerosol by a slow, deep inspiration,
`thereby
`effectively distributing the aerosolized medicament to the
`
`distal region of the lungs.
`
`A gas source will usually deliver a preselected
`volume of gas at greater than about 15 psig in order to produce
`a sonic velocity jet in an aerosol producing region (although
`sonic velocity is not always necessary).
`The pressurized gas
`is required to efficiently atomize the liquid or break apart
`the powder producing an aerosol having particles that are
`predominantly 1 to 5 pm in diameter.
`In addition, the volume
`of the gas bolus must be less than a fraction of a patient's
`inspiratory volume, preferably between 100 to 750 ml. Suitable
`gas sources include:
`
`
`
`1)
`
`an air compressor with a timer to control the
`
`operating period of the compressor (where the timer
`
`comprises at least a portion of the controller
`
`discussed hereinafter);
`
`a compressed gas cylinder with a solenoid valve
`
`controlled by a timer;
`
`a liquid propellant with a metering valve and an
`
`evaporation chamber;
`
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`10
`
`4)
`
`5)
`
`a spring piston pump; and
`
`a pneumatic pump.
`
`The means for producing the aerosol will usually
`
`consist of a constricted orifice that produces a high velocity
`
`gas flow to atomize a liquid or break apart powder
`
`agglomerates.
`
`The present invention is designed to be used
`
`with a conventional jet nebulizer that operate with airflow
`
`rates in the range from 3 to 13 L/min at about 15 psig, with
`
`the flow rate depending largely on the nozzle geometry of the
`
`nebulizer.
`
`The present invention further provides a means of
`
`controlling the volume of air delivered to the nebulizer in
`
`order to produce an aerosol bolus having a specific volume that
`
`can be contained in the aerosol holding chamber.
`
`By
`
`controlling the gas source to deliver a specific volume of gas,
`
`the system can employ a variety of nebulizers available from
`
`commercial vendors, such as Marquest, Hudson, Baxter, and
`
`Puritan Bennett.
`
`
`
`The present invention can also operate with a powder
`
`jet disperser as a means of generating an aerosol.
`
`A
`
`pressurized gas jet produces a highly turbulent gas flow that
`
`serves to break apart powder agglomerates producing an aerosol
`
`having single particles of the preformed powder. An example of
`
`a suitable powder/gas mixing chamber is a simple nozzle with a
`
`venturi ejector, as shown in Figure 7. An advantage of this
`
`type of powder mixer is that the gas flow through the nozzle is
`
`only a fraction of the entrained airflow through the venturi.
`
`This reduces the air capacity so that the required volume of
`
`gas for dispersing the powder could be delivered from a small
`
`I'pocket-sized" gas source.
`
`In addition,
`
`the powder dispersing apparatus must
`
`produce a pressure pulse having a long enough duration
`
`(typically 0.01 to 1 second)
`
`to adequately fluidize the powder
`
`and efficiently dispense the powder from the reservoir.
`
`A
`
`small diameter nozzle,
`
`less than 0.020 inch is acceptable and
`
`less than 0.015 inch is preferable,
`
`in order to achieve an
`
`acceptable duration of the pressure pulse at peak pressures
`exceeding 15 psig with a volume of gas that is small enough to
`be contained in a small holding chamber.
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 12 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 12 of 39
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`

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`WO 93/00951
`
`PCI‘/US92/05621
`
`11
`
`Referring now to the drawings wherein like numerals
`indicate like parts,
`the numeral 10 generally indicates an
`exemplary apparatus constructed in accordance with the
`principles of this invention.
`The apparatus is powered by an
`electrical source 12 that provides energy for a controller,
`typically in the form of a microprocessor 18.
`The present
`invention, however, does not require the use of an electrical
`or digital controller, so long as some means is provided for
`supplying preselected gas volumes for aerosol bolus.
`
`
`
`The microprocessor 18 is a general purpose
`microcontroller unit (MCU) such as that sold by Motorola under
`their Model Number 68HC05. This unit has on-chip peripheral
`capabilities and the on-board memory system 30.
`The on-chip
`peripheral capability of the Motorola unit includes multiple
`input ports, one of which receives the input data from the
`keypad 13 via line 16.
`The microprocessor 18 has a plurality
`of output ports and its functioning will be more fully
`understood as the components of the invention are described.
`Keypad 13 has six input keys that are important to
`performance, namely; 13a, 13b, 13c, 13d, 13a and 13f.
`The
`volume or amount of each aerosolized dose is selected by
`controlling the length of time a compressor 22 is turned on by
`pressing the "puff size" button 13a.
`The keypad 12 is
`programmed so that a first press of button 13a will display a
`choice of puff sizes on an LCD 32. Additional pressings of the
`button will select the desired size.
`A "puff counter actuator"
`button 13b is pressed which will cause the LCD 32 display "00".
`A second press of 13b energizes the air compressor 22 via
`output line 38 for a 13a. This produces the first aerosolized
`dose or bolus of a medicament for inhalation.
`The LCD display
`32 will change from 00 to 01 and the LCD will increase by one
`upon each additional activation of the compressor.
`The patient
`will continue activating puffs with button 13b until the
`prescribed number of puffs have been taken. As these puff
`events are occurring,
`the time and number are stored in
`memory 30.
`
`To view a record of previous uses of the device, a
`dosage recall button 13c is pressed which causes LCD 32 to
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 13 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 13 of 39
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`W0 93/00951
`
`PCT/U592/05621
`
`12
`
`display prior dates,
`
`times, puff sizes and number of puff
`
`formation events. Successive pressings of the button 13c will
`
`enable scrolling of the patient's dosage history. Reversal of
`
`scroll direction is accomplished by pressing button 13d and
`
`then continuing to scroll with 13c.
`
`The button 13e is a
`
`clock/calendar button. Pressing the button 13e causes the LCD
`
`32 to display the current date and time. After the device is
`
`used and a series of puffs have been taken,
`
`the system will
`
`automatically default five minutes after the last puff to
`
`display the actual time and date on the LCD display. Thus,
`
`the
`
`device is a clock/calendar when not in actual use and during
`
`the use and date or time can be viewed by pressing 13a.
`
`Air from compressor 22 is communicated to a mixer 40.
`
`The mixer 40 may be a nebulizer, a dry powder dispenser or
`
`other type of nebulizer known to the prior art. When unit 40
`
`is a dry powder dispenser,
`
`the compressed air from compressor
`
`22 may optionally be first subjected to coalescing filter 41
`
`and a desiccant filter 41a. When unit 40 is a nebulizer, a
`
`particle filter 21 may optionally be placed at the intake 23 of
`
`the compressor to filter out articles before the air is
`
`compressed.
`
`In either case,
`
`the medicament or drug will
`
`preferably be in the form of a small particulate, usually
`
`
`
`having an aerodynamic size in the range from 1 pm to 5 gm.
`
`It
`
`is known that particles in this size range are most efficiently
`
`delivered to the alveolar regions of the lungs.
`
`An exemplary dry powder venturi nozzle 200 is
`
`illustrated in Fig. 7.
`
`The venturi nozzle 200 includes a side
`
`port 202 which receives an initial charge of powder medicament
`
`H, typically a lyophilized protein or polypeptide.
`
`The powder
`
`is drawn into dispersion chamber 204 at the point where nozzle
`
`orifice 206 introduces a high velocity gas stream in the
`
`direction of arrow 208.
`
`The high velocity gas stream will
`
`result from pressurized gas or air in plenum 210, which may be
`
`provided by a separate air compressor 22 (Fig. 1) or an air or
`
`gas cylinder (not illustrated).
`
`The low pressure caused by the
`
`air or gas stream will draw the powder continuously into the
`
`dispersion chamber 204 where agglomerates of the powder are
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 14 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 14 of 39
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`

`

`WO 93/00951
`
`PCI‘/US92/05621
`
`13
`
`broken into smaller sizes within the preferred 1 pm to 5pm
`range by the turbulent shear effect in the chamber.
`
`In any event, unit 40 is of a type that will nebulize
`or mix a defined amount of medicant with the preselected amount
`of compressed air received from compressor 22. This defined
`
`amount, referred to as a dosage or bolus,
`flows into a chamber
`42 via the conduit 39.
`The chamber 42 is transparent,
`typically having a glass,
`transparent plastic, or similar
`wall 44.
`
`A critical aspect of the present invention is the
`ability to transfer the aerosolized medicament from the mixer
`40 into the chamber 42 without substantial loss of medicament
`through the mouthpiece or within the chamber.
`Such losses will
`be minimized so that at least about 40% by weight of the
`medicament delivered to the chamber will remain aerosolized and
`suspended within the chamber after the entire volume has been
`transferred. Preferably, at least about 55% will remain
`
`
`
`Such low losses
`suspended, more preferable at least about 70%.
`are desirable since the total amount of drug which may be
`introduced into the chamber for each transfer is maximized, and
`thus the amount which may be inhaled in each breath by a
`patient is increased. Additionally, even small losses of high
`valued drugs, such as proteins and polypeptides, can become
`significant over time. Still further,
`the ability to deliver a
`concentrated aerosol dispersion of drug into the chamber will
`increase the concentration of drug delivered to the patient
`with each breath.
`Such high concentration dosages are
`preferable since they can reduce the total number of breaths
`
`thus
`necessary to deliver a prescribed amount of drug,
`increasing the total amount of time required for the treatment.
`
`Loss of aerosolized medicament can be reduced by
`minimizing mixing between the aerosolized medicament and the
`displaced air as the chamber is being filled. Minimum mixing
`between the aerosol transferred from the mixing chamber 40 and
`the displaced air within chamber 42 can be enhanced by properly
`designing the chamber 42 as well as the inlet flow geometry of
`the aerosol into the chamber. Particularly preferred
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1012, p. 15 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01